Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. Following initial acute infection, a majority of infected individuals develop chronic hepatitis because HCV replicates preferentially in hepatocytes but is not directly cytopathic. Chronic hepatitis can progress to liver fibrosis leading to cirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma), making it the leading cause of liver transplantations. This and the number of patients involved, has made HCV the focus of considerable medical research. Replication of the genome of HCV is mediated by a number of enzymes, amongst which is HCV NS3 serine protease and its associated cofactor, NS4A, that mediate a number of proteolytic cleavages of the HCV polyprotein resulting in the generation of the HCV replication enzymes. NS3 serine protease is considered to be essential for viral replication and has become an attractive target for drug discovery.
Current anti-HCV therapy is based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin. Not only does this therapy result in a limited efficacy in that only part of the patients are treated successfully, but it also faces significant side effects and is poorly tolerated in many patients. Hence there is a need for more effective, convenient and better-tolerated therapy. There is a need for further HCV inhibitors that overcome the disadvantages of current HCV therapy such as side effects, limited efficacy, the emergence of resistance, as well as compliance failures.
Various agents have been described that inhibit HCV NS3 serine protease and its associated cofactor, NS4A. WO 05/073195 discloses linear and macrocyclic NS3 serine protease inhibitors with a central substituted proline moiety and WO 05/073216 with a central cyclopentyl moiety. Amongst these, the macrocyclic derivatives are attractive in that they show pronounced activity against HCV and a good pharmacokinetic profile.
It now has been found that a particular macrocyclic compound with a central quinolinyloxy substituted cyclopentyl moiety is particularly attractive in terms of potency as well as pharmacokinetics. This is the compound of formula (XVII), with the structure represented hereafter:

The compound of formula (XVII) is a very effective inhibitor of the Hepatitis C virus (HCV) serine protease and is described in WO 2007/014926, published on 8 Feb. 2007. Due to its favourable properties it has been selected as a potential candidate for development as an anti-HCV drug. Consequently there is a need for producing larger quantities of this active ingredient based on processes that provide the product in high yield and with a high degree of purity.
The present invention is concerned with processes for preparing the compound of formula (XVII), or a pharmaceutically acceptable salt thereof, with the preparation of intermediates used in these processes, and to certain of these intermediates.
The compound of formula (XVII) can be prepared by a metathesis reaction starting from an intermediate (XIV), which is cyclized to obtain an intermediate (XV), which is then hydrolyzed to the macrocyclic acid (XVI). The latter is coupled with a sulfonylamide (XVII) in an amide forming reaction, thus obtaining the end product (XVII), as outlined in the following reaction scheme:

The pharmaceutically acceptable salt forms of the compound of formula (XVII) can be prepared by reacting the free form of this compound with an acid or with a base.
In this and the following reaction schemes or representations of individual compounds, for example in compound (XIV), R is C1-4alkyl, in particular R is C1-3alkyl, more in particular R is C1-2alkyl, or in one embodiment R is ethyl. The reaction to convert (XV) into (XVI) is a hydrolysis reaction that preferably is conducted by using a base in an aqueous medium such as a mixture of water and a water-soluble organic solvent such as tetrahydrofuran (THF) or an alcohol, in particular the alcohol from which the ester in (XIV) is derived, or mixtures of such solvents. The base that is used can be an alkali metal hydroxide such as e.g. NaOH or KOH, and in particular can be LiOH.
Intermediate (XIV) is cyclized by an olefin metathesis reaction in the presence of a suitable metal catalyst such as e.g. an ylidene Ru-based catalyst, in particular an optionally substituted alkylidene or indenylidene catalyst, such as bis(tricyclohexylphosphine)-3-phenyl-1H-inden-1-ylidene ruthenium chloride (Neolyst M1®) or bis(tricyclohexylphosphine)[(phenylthio)methylene]ruthenium dichloride. Other catalysts that can be used are Grubbs first and second generation catalysts, i.e. benzylidene-bis(tricyclohexylphosphine)dichlororuthenium and (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene) (tricyclohexylphosphine)ruthenium, respectively. Of particular interest are the Hoveyda-Grubbs first and second generation catalysts, which are dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)-ruthenium(II) and 1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro-(o-isopropoxyphenylmethylene) ruthenium respectively. The metathesis reactions can be conducted in a suitable solvent such as for example an ether, e.g. THF, dioxane; halogenated hydrocarbons, e.g. dichoromethane, CHCl3, 1,2-dichloroethane and the like, hydrocarbons, e.g. toluene. In a preferred embodiment, the metathesis reaction is conducted in toluene.
Intermediate (XVI) can be coupled with cyclopropylsulfonamide by an amide forming reaction, such as by any of the procedures for the formation of an amide bond. In particular, (XVI) may be treated with a coupling agent, for example N,N′-carbonyl-diimidazole (CDI), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), N-isobutyloxy-carbonyl-2-isobutyloxy-1,2-dihydroquinoline (IIDQ), 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (EDCI), or benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (commercially available as PyBOP®), in a solvent such as an ether, e.g. THF, or a halogenated hydrocarbon, e.g. dichloromethane, chlorophorm, dichloroethane, and reacted with cyclopropyl-sulfonamide, preferably after reacting (XVI) with the coupling agent. The reactions of (XVI) with cyclopropylsulfonamide preferably are conducted in the presence of a base, for example a trialkylamine such as triethylamine or diisopropylethylamine, or 1,8-diazabicycle[5.4.0]undec-7-ene (DBU). Intermediate (XVI) can also be converted into an activated form, e.g. an activated form such as an acid halide, in particular an acid chloride or bromide, or an active ester, e.g. an acid esterified with an aryloxy group such as phenoxy, p.nitrophenoxy, pentafluorophenoxy, trichlorophenoxy, pentachlorophenoxy and the like; or by converting the macrocyclic acid (XVI) into a mixed anhydride.
The intermediates (XIV) are starting materials in the preparation of the compounds of formula (XVII) and hence there is a need to provide processes for preparing these intermediates in large scale production, i.e. at multikilogram scale, or larger. These processes should provide the end product in high yield and purity. In particular the presence of various chiral centers in the molecule poses particular challenges in that chiral purity is essential to have a product that is acceptable for therapeutic use. Hence the processes for preparing (XIV) should result in products of acceptable chiral purity without use of cumbersome purification procedures with the loss of substantial amounts of undesired stereoisomeric forms.
One of the aspects of this invention concerns processes for preparing the intermediates (XIV) in high yield and purity that are fit for large scale industrial application.
The invention also concerns intermediates that are useful in the preparation of the compounds of formula (XVII). A number of such intermediates are:
(I) (II) (III) (IV) (V) (Va) (Vb) (VI) (VII) (VIII) (IX) (X) (XI) (XII) (XIII) (XIV)
In the compounds listed in the above table, R1 is a specified hereinafter and R is as specified above. In one embodiment R1 is methyl. In another embodiment R is ethyl.
Honda et al., Tetrahedron Letters, vol. 22, no. 28, pp 2679-2682, 1981, describes the synthesis of (±)-brefeldin A using the following starting materials:

The synthesis of Honda et al. starts from dl-trans-4-oxocyclopentane-1,2-dicarboxylic acid (2), which was esterified to the corresponding methyl ester (3), and reduced with Raney-Ni to the alcohol (4). Partial hydrolysis of 4 and benzylation gave predominantly one diastereoisomer of the ester 5, namely that diastereoisomer wherein the hydroxyl and carboxylic acid groups are in cis position. The latter ester 5 in Honda et al. and compound (V) are both racemates, but are diastereoisomers of each other, more precisely epimers on the carbon nr. 4 bearing the hydroxy group. Compound (Va) is one of the two enantiomers obtained by separation from the racemic compound (V). The other enantiomer is compound (Vb).
WO 2005/073195 describes the synthesis of enantiomercally pure bicyclic lactone (8b) starting from an enantiomer of 3,4-bis(methoxycarbonyl)cyclopentanone. The latter was prepared as described by Rosenquist et al. in Acta Chemica Scandinavica 46 (1992) 1127-1129. The trans (3R,4R)-3,4-bis(methoxycarbonyl)cyclopentanone isomer was converted to the bicyclic lactone (8b):

WO 2005/073195 additionally describes further modification of lactone (8b) to the t.Bu ester, opening of the lactone and coupling with appropriately protected amino acids, e.g. with (1R,2S)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester, which in the latter instance yields:

The build-up of the compounds of formula (XVII) necessarily involves introducing the thiazolyl substituted quinoline moiety on the cyclopentyl ring via an ether linkage. The Mitsunobu reaction offers an attractive reaction route for preparing aromatic alkylethers in which an alkyl ether is activated and reacted with an aromatic alcohol. In addition, Mitsunobu reactions are in general more efficient than the O-arylation reactions, which require additional synthesis steps. In this mild reaction the stereochemistry of the alkyl part is inverted. The reaction gives rise to side products, such as R′OOC—NH—NH—COOR′, wherein R′ is C1-4alkyl and in particular ethyl or isopropyl, other nitrogen-containing compounds, and triphenylphosphine oxides, that need to be separated from the desired end product.
The processes of the present invention are advantageous in that they are suitable for large scale production. The number of cumbersome purification steps, in particular by chromatography, is reduced.
Furthermore, the choice of the protecting groups benzyl (Bn) and C1-4alkyl, in particular methyl (Me), in the compounds (V), (Va), and (Vb) allows the selective manipulation of these compounds. The benzyl ester or the C1-4alkyl ester (and in particular the methyl ester) can be selectively cleaved off because of the different reaction conditions used for removing a benzyl group or a C1-4alkyl group, in particular a methyl (Me) group. Moreover, the benzyl ester moiety in compound (IV), (V), or (Va) brings the advantage that it allows efficient separation of compounds (IV), (V), or (Va) by chiral chromatography, and it facilitates the analysis and detection of these compounds since the benzyl moiety is UV-active.